title: Antileishmanial activity, uptake, and biodistribution of an amphotericin B and poly(α-Glutamic Acid) complex.
abstract: A noncovalent, water-soluble complex of amphotericin B (AMB) and poly(α-glutamic acid) (PGA), with AMB loadings ranging from 25 to 55% (wt/wt) using PGA with a molecular weight range of 50,000 to 70,000, was prepared as a potential new treatment for visceral leishmaniasis (VL). The AMB-PGA complex was shown to be as active as Fungizone (AMB deoxycholate) against intracellular Leishmania donovani amastigotes in differentiated THP-1 cells. The in vitro uptake of the AMB-PGA complex by differentiated THP-1 cells was similar to that of Fungizone and higher than that of AmBisome (liposomal AMB). The AMB-PGA complex also displayed a dose-response profile similar to that of AmBisome in vivo in BALB/c mice against L. donovani, with 50% effective doses (ED50s) of 0.24 ± 0.03 mg/kg of body weight for the AMB-PGA complex and 0.24 ± 0.06 mg/kg for AmBisome. A biodistribution study with mice indicated that the AMB-PGA complex cleared more rapidly from plasma than AmBisome, with a comparable low level of distribution to the kidneys.
authors.affiliation: Department of Pharmaceutics, UCL School of Pharmacy, London, United Kingdom.
authors.forename: Abeer H A
authors.initials: AH
authors.lastname: Mohamed-Ahmed
authors.forename: Karin
authors.initials: K
authors.lastname: Seifert
authors.forename: Vanessa
authors.initials: V
authors.lastname: Yardley
authors.forename: Hollie
authors.initials: H
authors.lastname: Burrell-Saward
authors.forename: Stephen
authors.initials: S
authors.lastname: Brocchini
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011099:Polyglutamic Acid / Q000737:chemistry*
chemical_list: D000981:Antiprotozoal Agents; D004338:Drug Combinations; C068538:liposomal amphotericin B; D011099:Polyglutamic Acid; D000666:Amphotericin B